The present invention relates to a new pharmaceutical form of taxoid derivatives. More precisely, it relates to the oral administration of a compound of general formula (I) or a pharmaceutically acceptable salt or solvent thereof: 
in which:
Z represents a hydrogen atom or a radical of general formula: 
xe2x80x83in which:
R1 represents
a benzoyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms, alkyl radicals comprising 1 to 4 carbon atoms, alkoxy radicals comprising 1 to 4 carbon atoms, and trifluoromethyl radicals,
a thenoyl or furoyl radical,
a radical R2xe2x80x94Oxe2x80x94COxe2x80x94 in which R2 represents:
an alkyl radical comprising 1 to 8 carbon atoms,
an alkenyl radical comprising 2 to 8 carbon atoms,
an alkynyl radical comprising 3 to 8 carbon atoms,
a cycloalkyl radical comprising 3 to 6 carbon atoms,
a cycloalkenyl radical comprising 4 to 6 carbon atoms, or
a bicycloalkyl radical comprising 7 to 61 carbon atoms,
these radicals being optionally substituted with one or more identical or different substituents chosen from halogen atoms, hydroxyl radicals, alkoxy radicals comprising 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion comprises 1 to 4 carbon atoms, piperidino or morpholino radicals, 1-piperazinyl radicals which are optionally substituted at position 4 with an alkyl radical comprising 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl portion comprises 1 to 4 carbon atoms, cycloalkyl radicals comprising 3 to 6 carbon atoms, cycloalkenyl radicals comprising 4 to 6 carbon atoms, phenyl radicals which are optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms, alkyl radicals comprising 1 to 4 carbon atoms, and alkoxy radicals comprising 1 to 4 carbon atoms, cyano or carboxyl radicals, and alkoxycarbonyl radicals in which the alkyl portion comprises 1 to 4 carbon atoms,
a phenyl or xcex1- or xcex2-naphthyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms, alkyl radicals comprising 1 to 4 carbon atoms and alkoxy radicals comprising 1 to 4 carbon atoms,
a 5-membered aromatic heterocyclic radical, preferably chosen from furyl and thienyl radicals, or
a saturated heterocyclic radical comprising 4 to 6 carbon atoms, and optionally substituted with one or more identical or different alkyl radicals comprising 1 to 4 carbon atoms;
R3 represents
an unbranched or branched alkyl radical comprising 1 to 8 carbon atoms,
an unbranched or branched alkenyl radical comprising 2 to 8 carbon atoms,
an unbranched or branched alkynyl radical comprising 2 to 8 carbon atoms,
a cycloalkyl radical comprising 3 to 6 carbon atoms,
a phenyl or xcex1- or xcex2-naphthyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, phenyl, xcex1- or xcex2-naphthyl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, it being understood that the alkyl radicals and alkyl portions of radicals comprise 1 to 4 carbon atoms, and the alkenyl and alkynyl radicals comprise 2 to 8 carbon atoms, or
a 5-membered aromatic heterocyclic radical comprising one or more identical or different hetero atoms chosen from nitrogen, oxygen and sulphur atoms, and optionally substituted with one or more identical or different substituents chosen from halogen atoms and alkyl, phenyl, xcex1- or xcex2-naphthyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl and alkoxycarbonyl radicals, it being understood that the alkyl radicals and alkyl portions of radicals comprise 1 to 4 carbon atoms, and the alkenyl and alkynyl radicals comprise 2 to 8 carbon atoms;
R4 represents
an alkoxy radical comprising 1 to 6 carbon atoms in an unbranched or branched chain,
an alkenyloxy radical comprising,3 to 6 carbon atoms in an unbranched or branched chain,
an alkynyloxy radical comprising 3 to 6 carbon atoms in an unbranched or branched chain,
a cycloalkyloxy radical comprising 3 to 6 carbon atoms, or
a cycloalkenyloxy radical comprising 4 to 6 carbon atoms,
these radicals being optionally substituted with one or more identical or different halogen atoms or with an alkoxy radical comprising 1 to 4 carbon atoms, an alkylthio radical comprising 1 to 4 carbon atoms, a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion comprises 1 to 4 carbon atoms, a cyano or carbamoyl radical, or an N-alkylcarbamoyl or N,N-dialkylcarbamoyl radical in which each alkyl portion comprises 1 to 4 carbon atoms or in which each alkyl portion forms, with the nitrogen atom to which it is attached, a saturated 5- or 6-membered heterocyclic radical optionally comprising a second hetero atom chosen from oxygen, sulphur and nitrogen atoms, and optionally substituted with an alkyl radical comprising 1 to 4 carbon atoms, a phenyl radical or a phenylalkyl radical in which the alkyl portion comprises 1 to 4 carbon atoms;
R5 represents
an alkoxy radical comprising 1 to 6 carbon atoms in an unbranched or branched chain,
an alkenyloxy radical comprising 3 to 6 carbon atoms,
an alkynyloxy radical comprising 3 to 6 carbon atoms,
a cycloalkyloxy radical comprising 3 to 6 carbon atoms, or
a cycloalkenyloxy radical comprising 3 to 6 carbon atoms,
these radicals being optionally substituted with one or more identical or different halogen atoms or with an alkoxy radical comprising 1 to 4 carbon atoms, an alkylthio radical comprising 2 to 4 carbon atoms, a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion comprises 1 to 4 carbon atoms, a cyano or carbamoyl radical, or an N-alkylcarbamoyl or N,N-dialkylcarbamoyl radical in which each alkyl portion comprises 1 to 4 carbon atoms or in which each alkyl portion forms, with the nitrogen atom to which it is attached, a saturated 5- or 6-membered heterocyclic radical optionally comprising a second hetero atom chosen from oxygen, sulphur and nitrogen atoms, and optionally substituted with an alkyl radical comprising 1 to 4 carbon atoms, a phenyl radical or a phenylalkyl radical in which the alkyl portion comprises 1 to 4 carbon atoms.
Preferably, R3 is an aryl radical represented by a phenyl or xcex1- or xcex2-naphthyl radical optionally substituted with one or more identical or different atoms or radicals chosen from fluorine, chlorine, bromine, and iodine atoms, and alkyl, alkenyl, alkynyl, phenyl, xcex1- or xcex2-naphthyl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, it being understood that the alkyl radicals and alkyl portions of the other radicals comprise 1 to 4 carbon atoms, and the alkenyl and alkynyl radicals comprise 2 to 8 carbon atoms.
Preferably, R3 can also be a 5-membered aromatic heterocyclic radical comprising one or more identical or different hetero atoms chosen from nitrogen, oxygen and sulphur atoms, and optionally substituted with one or more identical or different substituents chosen from fluorine, chlorine, bromine, and iodine atoms, alkyl radicals comprising 1 to 4 carbon atoms, aryl radicals comprising 6 to 10 carbon atoms, alkoxy radicals comprising 1 to 4 carbon atoms, aryloxy radicals comprising 6 to 10 carbon atoms, amino radicals, alkylamino radicals comprising 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion comprises 1 to 4 carbon atoms, acylamino radicals in which the acyl portion comprises 1 to 4carbon atoms, alkoxycarbonylamino radicals comprising 1 to 4 carbon atoms, acyl radicals comprising 1 to 4 carbon atoms, arylcarbonyl radicals in which the aryl portion comprises 6 to 10 carbon atoms, cyano, carboxyl or carbamoyl radicals, alkylcarbamoyl radicals in which the alkyl portion comprises 1 to 4 carbon atoms, dialkylcarbamoyl radicals in which each alkyl portion comprises 1 to 4 carbon atoms or alkoxycarbonyl radicals in which the alkoxy portion comprises 1 to 4 carbon atoms.
Preferably, the radicals R4 and R5, which may be identical or different, represent unbranched or branched alkoxy radicals comprising 1 to 6 carbon atoms, and optionally substituted with a methoxy, ethoxy, ethylthio, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-pyrrolidinocarbonyl or N-piperidinocarbonyl radical.
More specifically, the present invention relates to the compounds of formula (I) in which Z represents a hydrogen atom or a radical of formula (II) in which R1 represents a benzoyl radical or a radical R2xe2x80x94Oxe2x80x94COxe2x80x94 in which R2 represents a tert-butyl radical; R3 represents an alkyl radical comprising 1 to 6 carbon atoms,an alkenyl radical comprising 2 to 6 carbon atoms, a cycloalkyl radical comprising 3 to 6 carbon atoms, a phenyl radical optionally substituted with one or more identical or different atoms or radicals chosen from fluorine and chlorine atoms, and methyl, methoxy, dimethylamino, acetylamino, tert-butoxycarbonylamino, trifluoromethyl, 2- or 3-furyl, 2- or 3-thienyl and 2-, 4- or 5-thiazolyl radicals; and R4 and R5, which may be identical or different, represent an unbranched or branched alkoxy radical comprising 1 to 6 carbon atoms.
Still more specifically, the present invention relates to the compounds of formula (I) in which Z represents a hydrogen atom or a radical of formula (II) in which R1 represents a benzoyl radical or a radical R2xe2x80x94Oxe2x80x94COxe2x80x94 in which R2 represents a tert-butyl radical, R3 represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl radical, and R4 and R5, which may be identical or different, represent a methoxy, ethoxy or propoxy radical.
Of even more special interest are the compounds of formula (I) in which Z represents a radical of formula (II) in which R1 represents a tert-butoxycarbonyl radical, R3 represents a phenyl radical, and R4 and R5, which may be identical or different, represent a methoxy, ethoxy or propoxy radical.
Still more particularly, the present invention relates to 4xcex1-acetoxy-2xcex1-benzoyloxy-5xcex2,20-epoxy-1xcex2-hydroxy-7xcex2,10xcex2-dimethoxy-9-oxo-11-taxen-13xcex1-yl (2R,3S)-3 tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of formula (Ia) 
It is known, from International Publication WO96/30355, the disclosure of which is incorporated by reference herein, how to prepare a compound according to the present invention by two processes. According to a first, multi-step process, 10-deacetylbaccatin III of formula (III): 
is selectively protected in positions 7 and 13, for example with a silyl diether, and then reacted with a compound of general formula (IV):
Rxe2x80x94Xxe2x80x83xe2x80x83(IV)
in which R represents a radical such that xe2x80x94OR has the same meaning as R4 defined above, and X represents a reactive ester residue such as a sulphuric or sulphonic ester residue or a halogen atom, to give a compound bearing the unit xe2x80x94OR in position 10 and silyl groups in positions 7 and 13. Next, the silyl protecting groups are replaced with hydrogen atoms to give a compound still bearing the group xe2x80x94OR in position 10 and xe2x80x94OH groups in positions 7 and 13. The latter derivative is etherified selectively in position 7 by reaction with the compound of formula (IV) in which R represents a radical such that xe2x80x94OR has the same meaning as R5 defined above, to give the compound of formula (I) in which Z is equal to hydrogen.
The next step comprises esterifying position 13, according to any known process in which the derivatives of formula (I), in which Z represents hydrogen, are reacted in the presence of a xcex2-lactam, for example, according to the process described in European patent 617,018, the disclosure of which is incorporated by reference herein, or in the presence of an oxazolidine as described, for example, in International Publication WO 96/30355 mentioned above. After deprotection of the protecting groups in positions 7 and 10, an ester of formula (I) is obtained in which Z is other than hydrogen and R represents hydrogen. The next step comprises reacting the positions 7 and 10 simultaneously by the action of a reagent formed in situ from a sulphoxide of formula (V) and acetic anhydride (Pummerer-type reaction):
Rxe2x80x94SOxe2x80x94Rxe2x80x83xe2x80x83(V)
in which R represents a radical such that xe2x80x94OR has the same meaning as R4 or R5 defined above, to form an alkylthioalkyloxy-type intermediate on positions 7 and 10.
The final step, which allows the desired compound of formula (Ia) to be obtained, is carried out on the intermediate compound obtained above, by the action of activated Raney nickel.
Generally, the action of the reagent formed in situ from a sulphoxide of formula (V), preferably dimethyl sulphoxide and acetic anhydride, is carried out in the presence of acetic acid or an acetic acid derivative such as haloaetic acid, at a temperature ranging from 0 to 50xc2x0 C.
Generally, the action of the activated Raney nickel in the presence of an aliphatic alcohol or an ether is carried out at a temperature of between xe2x88x9210 and 60xc2x0 C.
In French patent application FR 97-14442, the disclosure of which is incorporated by reference herein, another process for preparing a derivative according to the present invention has been described. This process allows, in a single step, the direct, selective and simultaneous alkylation of the two hydroxyl functions in positions 7 and 10 of formula (VI) below: 
in which A represents hydrogen or a side chain of formula (IIa) below: 
in which G represents a hydroxy protecting group, and R1 and R3 have the same meaning as in formula (II) above, or an oxazolidine unit of formula (IIb): 
in which R1 and R3 have the same meaning as in formula (II), and Ra and Rb, which may be identical or different, represent hydrogen or alkyl, aryl, halo, alkoxy, arylalkyl, alkoxyaryl, haloalkyl, or haloaryl substituents, it being possible for the substituents to optionally form a 4- to 7-membered ring.
It is preferred to use 10-deacetylbaccatin, i.e., the product of formula (III), as starting material, as the resulting process is more economical. It also avoids the intermediate protection and deprotection steps necessary in the known processes.
The hydroxy protecting groups G in formula (IIa) can be chosen from all of the hydroxy protecting groups described in books such as Greene and Wuts, Protective Groups in Organic Synthesis, 1991, John Wiley and Sons, and MacOmie, Protective Groups in Organic Chemistry, 1975, Plenum Press, the disclosures of which are incorporated by reference herein, so long as they can be deprotected under conditions which minimally degrade, or do not degrade, the rest of the molecule. For example, the following protecting groups may be used:
ethers, preferably ethers such as methoxymethyl ether, 1-ethoxyethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, benzyl ethers optionally substituted with one or more identical or different groups such as methoxy, chloro, or nitro, 1-methyl-1-methoxyethyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether and silyl ethers such as trialkylsilyl ethers, and
carbonates such as trichlorethyl carbonates.
More particularly, the radicals Ra and Rb of formula (IIb) are chosen from those described in International Publication WO 94/07878, the disclosure of which is incorporated by reference herein. The derivatives more particularly preferred are those in which Ra is hydrogen and Rb is a p-methoxyphenyl radical.
The alkylating agent is chosen from:
alkyl halides, preferably from alkyl iodides (RI),
alkyl sulphates, such as methyl sulphate, and
oxoniums, such as trialkyloxonium boric salts, in particular trimethyloxonium tetrafluoroborate (Me3OBF4).
Methyl iodide is preferably used as the alkylating agent.
The alkylating agent is used in the presence of an anionization agent such as one or more strong bases, in anhydrous medium.
Among the bases which can be used in anhydrous medium, mention may be made of:
alkali metal hydrides, such as sodium or potassium hydride,
alkali metal alkoxides, such as potassium tert-butoxide,
silver oxide Ag2O,
1,8-bis(dimethylamino)naphthalene, and
mono- or dimetallic base mixtures, such as those described, for example, in publications such as P. Caubxc3xa8re Chem. Rev. 1993, 93, 2317-2334. or M. Schlosser Mod. Synth. Methods (1992), 6, 227-271, the disclosures of which are incorporated by reference herein. The alkyllithium/alkali metal t-butoxide or alkali metal amide/alkali metal t-butoxide combinations are particularly preferred. One of the two bases can be generated xe2x80x9cin situxe2x80x9d.
Among all of the possible combinations of alkylating agent and anionization agent, it is preferred to use methyl iodide in the presence of potassium hydride.
The reaction is preferably carried out in an organic medium which is inert under the reaction conditions. Among the solvents, it is preferred to use:
ethers such as tetrahydrofuran or dimethoxyethane;
when silver oxide is used as the anionization agent, it is preferred to use polar aprotic solvents such as dimethylformamide, or aromatic solvents such as toluene; and
when 1,8-bis(dimethylamino)naphthalene is used as the anionization agent, it is preferred to use alkylesters such as ethylacetate.
Preferably, the molar ratio between the anionization agent and the substrate is greater than 2, and more preferably ranges from 2 to 20.
It is also preferred that the molar ratio between the alkylating agent and the substrate is greater than 2, and preferably ranges from 2 to 40.
It is preferred to use a reaction temperature ranging from xe2x88x9230xc2x0 C. to 80xc2x0 C.
The reaction time advantageously ranges from a few hours to 48 hours depending on the reagents chosen.
After the alkylating step is carried out on 10-deacetylbaccatin, the resulting compound can then be esterified according to known processes, for example, those described in European patent EP 617,018 or International Publication WO 96/30355, mentioned above.
Thus, according to a first, 3-step process, the procedure begins with the dialkylation of 10-deacetylbaccatin, using an alkylating agent in the presence of a strong base. In the second step, described in European patent 617,018 mentioned above, the 10-deacetylbaccatin dietherified in positions 7 and 10 is coupled, in position 13, with a suitably protected xcex2-lactam in the presence of an activating agent chosen from tertiary amines and metal bases which ensure the formation of an alkoxide in position 13. Deprotection of the side chain is then achieved by the action of an inorganic or organic acid.
According to a second, 3-step process, the procedure can also begin with the dialkylation of 10-deacetylbaccatin, using an alkylating agent in the presence of a strong base. However, in the second step, described in International Publication WO 96/30355, the 10-deacetylbaccatin dietherified in positions 7 and 10 is coupled, in position 13, with an oxazolidine in the presence of a coupling agent such as diimides in the presence of an activating agent such as dialkylaminopyridines. Opening of the oxazolidine is achieved by the action of an inorganic or organic acid.
According to a third process, a baccatin suitably protected in positions 7 and 10 is esterified in position 13 with a xcex2-lactam or an oxazolidine in the presence of a coupling agent and/or an activating agent as described in the above two processes. After deprotection in positions 7 and 10, the dietherification in positions 7 and 10 is carried out by an alkylating agent in the presence of a strong base. Deprotection of the side chain is then achieved by the action of an inorganic or organic acid.
Formulations suitable for oral administration mean formulations which are in a form suitable to be administered orally to a patient. The formulations may be presented as any suitable oral dosage form, such as, for example, capsules, cachets or tablets, each comprising a predetermined amount of the active ingredient, a powder or granules, a solution or a suspension in an aqueous liquid or a non-aqueous liquid, and an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
Pharmaceutical composition means a composition comprising a compound of formula (I) and at least one component chosen from pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures of these substances. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. Examples of suitable carriers, diluents, solvents or vehicles include water, ethanol, polyols, vegetable oils (such as olive oil), organic esters such as ethyl oleate, and suitable mixtures thereof. Examples of excipients include lactose, milk, sugar, sodium citrate, calcium carbonate, and dicalcium phosphate. Examples of disintegrating agents include starch, alginic acids and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulphate, talc, and high molecular weight polyethylene glycols.
Liquid dosage form means that the dose of the active compound to be administered to the patient is in liquid form, such as, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan and phospholipids, a mixture of these substances, and the like.
Solid dosage form means the dosage form of the compound according to the invention is in solid form, such as, for example, capsules, tablets, pills, powders, dragees or granules. In such solid dosage forms, the compound according to the invention is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or with (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, for example, glycerol, (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution retarders, for example paraffin, (f) absorption accelerators, for example, quaternary ammonium compounds, (g) wetting agents, for example, acetyl alcohol and glycerol monostearate, (h) adsorbents, for example, kaolin and bentonite, (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols and sodium lauryl sulfate, (j)pacifying agents, (k) buffering agents, or agents which release the compound according to the invention in a certain part of the intestinal tract in a delayed manner.